Focal microvascular lesions ? such as microinfarcts and microhemorrhages ? are frequently observed in the brains of older individuals and are strongly associated with cognitive impairment and dementia. Yet, the underlying pathophysiological mechanisms and structural and functional consequences of these lesions are poorly understood. This proposal aims to unravel the mechanisms underlying microvascular lesion formation and their impact on local and remote vascular and neuronal networks, in the context of cerebral amyloid angiopathy (CAA). CAA is one of the most common age-related cerebral small vessel diseases, characterized by the accumulation of amyloid ? in small cortical arterioles. It has been suggested that vascular amyloid deposition involves a self-reinforcing cycle of vascular smooth muscle cell degeneration and impaired perivascular clearance of solutes (including amyloid) from the brain, which eventually results in the formation of microinfarcts and microhemorrhages. Although CAA has traditionally been considered a local disease resulting in focal lesions from individually affected cortical vessels, recent preliminary observations suggest profound alterations in surrounding vascular and neuronal networks, with more remote brain tissue injury as a result. The proposed research will address these network-wide effects of local vascular amyloid accumulation, by combining advanced neuroimaging and histopathology techniques in ex vivo human brains with cutting- edge optical imaging tools in living mice. The proposal builds on the applicants? international leadership in CAA, their strong background in post-mortem MRI and state-of-the-art histopathology techniques, and pioneering work in two-photon microscopy of mouse models with CAA. Combined with the world-class resources and international collaborations with experts in the field to perform advanced image processing, the proposed set of experiments will likely yield much needed answers regarding the mechanisms involved in cerebral small vessel disease. Novel insights resulting from this project may also yield promising new targets to prevent vascular cognitive impairment and dementia in the elderly.